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Cell Mol Neurobiol. 2019 Mar;39(2):265-286. doi: 10.1007/s10571-018-00646-4. Epub 2019 Jan 3.

MALAT1 Up-Regulator Polydatin Protects Brain Microvascular Integrity and Ameliorates Stroke Through C/EBPβ/MALAT1/CREB/PGC-1α/PPARγ Pathway.

Author information

1
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, People's Republic of China.
2
College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian, 116044, People's Republic of China.
3
Department of Neurology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
4
Center for Drug Screening and Pharmacodynamics Evaluation, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China.
5
Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing, 210009, People's Republic of China.
6
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, 20057, USA.
7
College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian, 116044, People's Republic of China. powerleishi@126.com.
8
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, People's Republic of China. tpang@cpu.edu.cn.
9
Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing, 210009, People's Republic of China. tpang@cpu.edu.cn.
10
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, 20057, USA. tpang@cpu.edu.cn.

Abstract

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA contributing to protect the blood-brain barrier (BBB) after stroke. We searched for small molecules that may up-regulate MALAT1 and focused on polydatin (PD), a natural product, as a possible candidate. PD enhanced MALAT1 gene expression in rat brain microvascular endothelial cells, reducing cell toxicity and apoptosis after oxygen and glucose deprivation (OGD). These effects correlated with reduction of inflammatory factors and enhancement of expression of BBB markers. We found opposite changes after MALAT1 silencing. We determined that C/EBPβ is a key transcription factor for PD-mediated MALAT1 expression. PPARγ activity is involved in MALAT1 protective effects through its coactivator PGC-1α and the transcription factor CREB. This suggests that PD activates the MALAT1/CREB/PGC-1α/PPARγ signaling pathway to protect endothelial cells against ischemia. PD administration to rats subjected to brain ischemia by transient middle cerebral artery occlusion (tMCAO) reduced cerebral infarct volume and brain inflammation, protected cerebrovascular endothelial cells and BBB integrity. These effects correlated with increased expression of MALAT1, C/EBPβ, and PGC-1α. Our results strongly suggest that the beneficial effects of PD involve the C/EBPβ/MALAT1/CREB/PGC-1α/PPARγ pathway, which may provide a novel therapeutic strategy for brain ischemic stroke.

KEYWORDS:

Cerebrovascular endothelial cells; Ischemic stroke; MALAT1; Polydatin

PMID:
30607811
DOI:
10.1007/s10571-018-00646-4

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